Rheumatoid Arthritis (RA) is a chronic inflammatory disease of unknown cause that leads to pain, stiffness, swelling and limitation in the motion and function of multiple joints. If left untreated, RA can produce serious destruction of joints that frequently leads to permanent disability. RA currently has a worldwide distribution with an estimated prevalence of 0.5 to 1%.
The main symptom of RA is the persistent inflammation of the joints, usually in a symmetric distribution. This inflammation leads to the destruction of cartilage, bone erosion and structural changes in the joint, which may range from minimal joint damage to debilitating disease. Some patients also experience the effects of RA in places other than the joints.
RA is a chronic disorder for which no cure currently exists. The major goals of treatment are to reduce pain and discomfort, prevent deformities, and minimize loss of joint function to maintain a productive and active life. For treatment to be considered successful, inflammation must be suppressed. Many pathways involved in the generation of the disease have been recognized and some of these have been unequivocally identified as important by therapeutic proof of principle studies. Major pharmacological treatments for RA include, but are not limited to, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs), including biologicals.
NSAIDs are typically given at the onset of symptoms and serve to reduce inflammation and pain thereby improving function. NSAIDs relieve symptoms but do not slow disease progression, so patients will eventually need additional or replacement therapies. Thus, DMARDs are typically added to the treatment regimen soon after diagnosis. The goal of DMARD use is to slow down the progression of disease. Methotrexate (MTX) (Merck Index 12th Ed., #6065) is currently the most commonly prescribed first-line DMARD. However, the administration of MTX has been associated with serious side effects such as skin reactions, pulmonary pneumonitis, gastrointestinal disturbances, hepatotoxicity and renal toxicity. The second leading oral DMARD is leflunomide (ARAVA®). However, as with MTX, leflunomide has been shown to have serious side effects including hepato- and haematological toxicity as well as pulmonary pneumonitis.
A number of biologicals have recently been approved for clinical treatment of RA. These drugs (proteins, e.g., monoclonal antibodies) prevent in general pro-inflammatory cytokines, in particular TNF-α and IL-1, from interacting with their receptors. Biologicals are often added to the treatment regimen once DMARD therapy is no longer adequate, or side effects have become unmanageable. The most commonly prescribed biologicals, e.g., infliximab (REMICADE®), block tissue necrosis factor-alpha (TNF-α), which is a pro-inflammatory cytokine produced by macrophages and lymphocytes. The pro-inflammatory effects of TNF-α suggest that inhibition of TNF-α would be clinically useful in RA. Indeed, clinical trial data has confirmed the efficacy of these TNF inhibitors in relieving the signs and symptoms of RA. However, these biologicals have potentially severe side effects including severe infections, sepsis, tuberculosis and fatal liver toxicity.
Dihydroorotate dehydrogenase (DHODH) catalyzes the conversion of dihydroorotate to orotate concurrent with the reduction of ubiquinone. DHODH controls the rate limiting step in the de novo pyrimidine biosynthesis. DHODH inhibition results in decreased cellular levels of ribonucleotide uridine monophosphate (rUMP), thus arresting proliferating cells in the G1 phase of the cell cycle. The inhibition of de novo pyrimidine nucleotide synthesis is of great interest in view of the observations that lymphocytes seem not to be able to undergo clonal expansion when this pathway is blocked.
Two major compound classes of mammalian DHODH inhibitors have been described in the literature. These are represented by brequinar (Merck Index 12th Ed., #1394), of formula
and the active metabolite A771726 of leflunomide, of formula
Proof of concept for DHODH inhibition has been established for brequinar. Indeed, biochemical and x-ray crystallographic studies have demonstrated that brequinar is a competitive inhibitor versus the co-factor ubiquinone.
WO 2005/075410 discloses anthranilic acid derivatives of general formula (A)
This PCT application concerns compounds which inhibit DHODH, useful for preventing and treating acute and chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, transplant rejection and malignant neoplastic disease. The type and position of the R2/R3 substitution are stated to be crucial for a strong DHODH inhibition. Compounds wherein R2/R3 are lipophilic substituents with high π-values in the range of 0.5 to 2 (Kubinyi, 1993) are said to display maximal inhibition. Moreover, monosubstitution, i.e., R3 is hydrogen, is indicated to be superior to di-substitution, the position of the monosubstitution being important for the effect. Thus, in monosubstituted compounds, the ortho-substitution is stated to be superior to meta-substitution, and far superior to substitution in the para-position. In a preferred embodiment of WO 2005/075410, X is CH2, O, S, CH═CH, OCH2, CH2O or CH2S, and R2 and R3 are the same or different and represent hydrogen or substituents in the 2-, 3- or 5-positions. In a more preferred embodiment of WO 2005/075410, X is OCH2, Y is hydrogen, R2 is a substituent in the ortho-position and is trifluoromethyl, and R3 is hydrogen. In a further preferred embodiment of said application, X is O, Y is hydrogen, and R2 and R3 are substituents in the meta- and meta′-positions, and are trifluoromethyl.
EP0497740 discloses benzyloxyphenyl derivatives of general formula (B)
This patent concerns compounds possessing antihyperproliferative/anti-inflammatory and anticancer activity. In a preferred group of compounds, R1 and R3 are methoxy, and the benzyloxy moiety is in meta-position in respect to R6. R6 is carboxy or an ester group, R5 is hydroxy or acetylamino, especially hydroxy.
EP0815087 discloses trisubstituted phenyl derivatives of general formula (C)
This patent concerns compounds for the treatment of inflammatory and proliferative skin diseases and cancer. The compounds are to be administered topically or in divided doses up to four times a day. In the most preferred compounds, R1 and R2 are methoxy, W is CH2CH2, and R3 and R4 together with the phenyl ring form a condensed ring system. Research Disclosure, 1998, 409(May), P561-P562 (No. 40953) discloses synthetic analogues of the natural product lavendustin A, of general formula (D)
Compounds are disclosed wherein R1 and R2 are the same or different and represent alkoxy, alkyl or alkenyloxy, R3 is i.a. alkoxy and R4 is i.a. acylamino.
Gennari et al., (1994) reported an anaerobic degradation in soil of 2-nitrophenoxy acids used as herbicides, e.g., acifluorfen, (Merck Index 12th Ed., #111) that gives compound E
There is no teaching in the literature disclosing the use of compound E as a pharmaceutical agent.